(1/457) Decreased hexosamine biosynthesis in GH-deficient dwarf rat muscle. reversal with GH, but not IGF-I, therapy.

Enhanced glucose flux via the hexosamine biosynthesis pathway (HNSP) has been implicated in insulin resistance. We measured L-glutamine:D-fructose-6-phosphate amidotransferase activity (GFAT, a rate-limiting enzyme) and concentrations of UDP-N-acetyl hexosamines (UDP-HexNAc, major products of HNSP) in muscle and liver of growth hormone (GH)-deficient male dwarf (dw) rats. All parameters measured, except body weight, were similar in 5-wk-old control and dw rats. Muscle GFAT activity declined progressively with age in controls and dw rats but was consistently 30-60% lower in 8- to 14-wk-old dw rats vs. age-matched controls; UDP-HexNAc concentrations in muscle were concomitantly 30% lower in dw rats vs. controls (P < 0.01). Concentrations of UDP-hexoses, GDP-mannose, and UDP in muscle were similar in control and dw rats. Muscle HNSP activity was similarly diminished in fed and fasted dw rats. In liver, only a small difference in GFAT activity was evident between controls and dw rats, and no differences in UDP-HexNAc concentrations were observed. Treatment with recombinant human GH (rhGH) for 5 days restored UDP-HexNAc to control levels in dw muscles (P < 0.01) and partially restored GFAT activity. Insulin-like growth factor I treatment was ineffective. We conclude that GH participates in HNSP regulation in muscle.  (+info)

(2/457) High-resolution physical and genetic mapping of the critical region for Meckel syndrome and Mulibrey Nanism on chromosome 17q22-q23.

Previously, we assigned the genes for two autosomal recessive disorders, Meckel syndrome (MKS; MIM 249000) and Mulibrey Nanism [MUL (muscle-liver-brain-eye Nanism); MIM 253250] that are enriched in the Finnish population, to overlapping genomic regions on chromosome 17q. Now, we report the construction of a bacterial clone contig over the critical region for both disorders. Several novel CA-repeat markers were isolated from these clones, which allowed refined mapping of the MKS and MUL loci using haplotype and linkage disequilibrium analysis. The localization of the MKS locus was narrowed to <1 cM between markers D17S1290 and 132-CA, within an approximately 800-kb region. The MUL locus was refined into an approximately 1400-kb interval between markers D17S1290 and 52-CA. The whole MKS region falls within the MUL region. In the common critical region, the conserved haplotypes were different in MKS and MUL patients. A trancript map was constructed by assigning expressed sequence tags (ESTs) and genes, derived from the human gene map, to the bacterial clone contig. Altogether, four genes and a total of 20 ESTs were precisely localized. These data provide the molecular tools for the final identification of the MKS and the MUL genes.  (+info)

(3/457) The bcl-2 knockout mouse exhibits marked changes in osteoblast phenotype and collagen deposition in bone as well as a mild growth plate phenotype.

Histological examination of long bones from 1-day-old bcl-2 knockout and age-matched control mice revealed no obvious differences in length of bone, growth plate architecture or stage of endochondral ossification. In 35-day-old bcl-2 knockout mice that are growth retarded or 'dwarfed'. the proliferative zone of the growth plate appeared slightly thinner and the secondary centres of ossification less well developed than their age-matched wild-type controls. The most marked histological effects of bcl-2 ablation were on osteoblasts and bone. 35-day-old knockout mouse bones exhibited far greater numbers of osteoblasts than controls and the osteoblasts had a cuboidal phenotype in comparison with the normal flattened cell appearance. In addition, the collagen deposited by the osteoblasts in the bcl-2 knockout mouse bone was disorganized in comparison with control tissue and had a pseudo-woven appearance. The results suggest an important role for Bcl-2 in controlling osteoblast phenotype and bone deposition in vivo.  (+info)

(4/457) 47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative SRS gene from a 7p13-q11 region.

Maternal uniparental disomy for chromosome 7 (UPD7) may present with a characteristic phenotype reminiscent of Silver-Russell syndrome (SRS). Previous studies have suggested that approximately 10% of SRS patients have maternal UPD7. We describe a girl with a mos47,XX,+mar/46,XX karyotype associated with the features of SRS. Chromosome painting using a chromosome 7 specific probe pool showed that the small marker was a ring chromosome 7 (r(7)). PCR based microsatellite marker analysis of the patient detected only one maternal allele at each of 16 telomeric loci examined on chromosome 7, but showed both paternal and maternal alleles at four centromeric loci. Considering her mosaic karyotype composed ofdiploid cells and cells with partial trisomy for 7p13-q11, the allele types obtained at the telomeric loci may reflect the transmission of one maternal allele in duplicate, that is, maternal UPD7 (complete isodisomy or homodisomy 7), whereas those at the centromeric loci were consistent with biparental contribution to the trisomic region. It is most likely that the patient originated in a 46,XX,r(7) zygote, followed by duplication of the maternally derived whole chromosome 7 in an early mitosis, and subsequent loss of the paternally derived ring chromosome 7 in a subset of somatic cells. The cell with 46,XX,r(7) did not survive thereafter because of the monosomy for most of chromosome 7. If the putative SRS gene is imprinted, it can be ruled out from the 7p11-q11 region, because biparental alleles contribute to the region in our patient.  (+info)

(5/457) Investigation of a unique male and female sibship with Kallmann's syndrome and 46,XX gonadal dysgenesis with short stature.

A sibship is described where the brother and a sister both have Kallmann's syndrome (anosmia and deficiency of gonadotrophin releasing hormone) and the woman also has streak ovaries. Although there are several conditions that may occur with Kallmann's syndrome, there are no known reports of ovarian dysgenesis being associated with this disorder. Cytogenetic analysis showed no rearrangement or major deletions of the chromosomes. Linkage analysis using informative microsatellite markers predicts that a gene other than KAL1 (at Xp22.3) is implicated in the Kallmann's syndrome manifesting concurrently with ovarian dysgenesis found in this family.  (+info)

(6/457) A missense mutation in the GHR gene of Cornell sex-linked dwarf chickens does not abolish serum GH binding.

Sex-linked dwarfism (SLD) in chickens is characterized by impaired growth despite normal or supranormal plasma growth hormone (GH) levels. This resistance to GH action is thought to be due to mutations of the GH receptor (GHR) gene that reduce or prevent GH binding to target sites. The genetic lesion causing GH resistance in Cornell SLD chickens is, however, not known. Previous studies have shown that hepatic GH-binding activity is abnormally low in these birds, yet the GHR gene is transcribed into a transcript of appropriate size and abundance. Point mutations or defects in translation could therefore account for the impaired GHR activity in this strain. These possibilities were addressed in the present study. A missense mutation resulting in the substitution of serine for the conserved phenylalanine was identified in the region of the GHR cDNA encoding the extracellular domain. Translation of this mutant transcript was indicated by the presence of GHR/GH-binding protein (GHBP)-immunoreactive proteins in liver (55, 70 and 100 kDa) and serum (70 kDa) of normal (K) and SLD birds. Radiolabelled GH did not, however, bind to the hepatic membranes of most SLD chickens. Serum GH-binding activity, in contrast, was readily detectable, although at significantly lower levels than in normal birds. The missense mutation in the SLD GHR gene may thus affect targeting of GHRs to hepatic plasma membranes.  (+info)

(7/457) Increased anxiety and impaired pain response in puromycin-sensitive aminopeptidase gene-deficient mice obtained by a mouse gene-trap method.

A mouse mutation, termed goku, was generated by a gene-trap strategy. goku homozygous mice showed dwarfism, a marked increase in anxiety, and an analgesic effect. Molecular analysis indicated that the mutated gene encodes a puromycin-sensitive aminopeptidase (Psa; EC 3. 4.11.14), whose functions in vivo are unknown. Transcriptional arrest of the Psa gene and a drastic decrease of aminopeptidase activity indicated that the function of Psa is disrupted in homozygous mice. Together with the finding that the Psa gene is strongly expressed in the brain, especially in the striatum and hippocampus, these results suggest that the Psa gene is required for normal growth and the behavior associated with anxiety and pain.  (+info)

(8/457) A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?

To investigate whether the expansion of CAG repeats of the TATA-binding protein (TBP) gene is involved in the pathogenesis of neurodegenerative diseases, we have screened 118 patients with various forms of neurological disease and identified a sporadic-onset patient with unique neurologic symptoms consisting of ataxia and intellectual deterioration associated with de novo expansion of the CAG repeat of the TBP gene. The mutant TBP with an expanded polyglutamine stretch (63 glutamines) was demonstrated to be expressed in lymphoblastoid cell lines at a level comparable with that of wild-type TBP. The CAG repeat of the TBP gene consists of impure CAG repeat and the de novo expansion involves partial duplication of the CAG repeat. The present study provides new insights into sporadic-onset trinucleotide repeat diseases that involve de novo CAG repeat expansion.  (+info)